N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮的手性拆分Enantioselective Resolution of N-(tert-Butoxycarbonyl)- 2-azabicyclo[2.2.1]hept-5-en-3-one
李普瑞,胡建建,王晓川,张玲玲,王晓钟
摘要(Abstract)：
(-)-(1R,4S)-N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮是抗艾滋病药物阿巴卡韦的重要中间体。今以2-氮杂双环[2.2.1]庚-5-烯-3-酮为原料,先与(Boc)2O反应生成外消旋体(±)-N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮,再以固定化脂肪酶作为拆分试剂选择性拆分制得。试验中分别使用了三种酶,三种酶均表现出较好的反应活性和较高的反应收率,其中固定化酶Lipozyme RM IM的反应活性最高,对其催化的酶促反应进行了优化,得到最佳的反应条件:以异丙醚为反应溶剂,酶与底物质量投料比为1.5/2.0,反应温度为30℃,收率46.5%,对映体过量大于99%。结构经1H-NMR确证。该方法成本低,酶的选择性、催化活性和反应收率高。
关键词(KeyWords)： 阿巴卡韦;N-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚-5-烯-3-酮;固定化脂肪酶;手性拆分
基金项目(Foundation):
作者(Author): 李普瑞,胡建建,王晓川,张玲玲,王晓钟
参考文献(References)：
- [1]ForróE,Fül p F.Enzymatic method for the synthesis of blockbuster drug intermediates–synthesis of five-membered cyclicγ-Amino acid andγ-lactam enantiomers[J].Eur J Org Chem,2008,2008(31):5263-5268.
- [2]Mahmoudian M,Lowdon A,Jones M,et al.A practical enzymatic procedure for the resolution of N-substituted 2-azabicyclo[2.2.1]hept-5-en-3-one[J].Tetrahedron:Asymmetry,1999,10(6):1201-1206.
- [3]Daluge S M.Preparation of purinylcyclopentenemethanol derivatives as medical antivirals:EP,434 450[P].1991-06-26.
- [4]Taylor S J C,Alan G S,Carol Lee,et al.Chemoenzymatic synthesis of(-)-carbovir utilizing a whole cell catalysed resolutionof2-azabicyclo[2.2.1]hept-5-en-3-one[J].J Chem Soc,Chem Commun,1990(16):1120-1121.
- [5]YUAN Fang(袁方),YAO Yi-ming(姚亦明),HAN Guo-xi a(韩国霞),et al.The synthesis of chiral carbon ring intermediate of abacavir(阿巴卡韦的手性碳环中间体的合成方法):CN,200 810 123 861[P].2008-10-15.
- [6]Csuk R,D?rr P.Biocatalytical transformations.IV.Enantioselective enzymatic hydrolyses of building blocks for the synthesis of carbocyclic nucleosides[J].Tetrahedron:Asymmetry,1994,5(2):269-276.
- [7]Kiss L,ForróE,Sillanp??R,et al.Synthesis of highly functionalized cyclopentanes as precursors of hydroxylatedazidocarbonucleosides[J].Synth,2010,2010(1):153-160.
- [8]Taylor S J,Brown R C,Keene P A,et al.Novel screening methods-the key to cloning commercially successful biocatalysts[J].Bioorg Med Chem,1999,7(10):2163-2168.
- [9]Mitsuda S,Umemura T,Hirohara H.Preparation of an optically pure secondary alcohol of synthetic pyrethroids using microbial lipases[J].Appl Microbiol Biotechnol,1988,29(4):310-315.
- [10]CAO Shu-gui(曹淑桂),LIU Zhan-bin(刘占斌),FENG Yan(冯雁),et al.Esterification and transesterification catalyzed by lipase in organic solvents(脂肪酶在有机溶剂中催化酯合成和酯交换反应)[J].Chem J Chinese U(高等学校化学学报),1991,12(11):1555-1557.
- [11]DING Yong-xue(丁永学),ZHANG Ming-jun(张铭俊),YU Xing-ju(虞星炬).Research of enzyme catalyzed resolution in organic phase to transesterification(有机相酶催化酯交换反应拆分环戊烯酮的研究)[J].Chem Bull(化学通报),2000(6):46-49.